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Q64536 (PDK2_RAT) Reviewed, UniProtKB/Swiss-Prot

Last modified January 22, 2014. Version 113. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial

EC=2.7.11.2
Alternative name(s):
PDK P45
Pyruvate dehydrogenase kinase isoform 2
Short name=PDH kinase 2
Gene names
Name:Pdk2
OrganismRattus norvegicus (Rat) [Reference proteome]
Taxonomic identifier10116 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus

Protein attributes

Sequence length407 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Serine/threonine kinase that plays a key role in the regulation of glucose and fatty acid metabolism and homeostasis via phosphorylation of the pyruvate dehydrogenase subunits PDHA1 and PDHA2. This inhibits pyruvate dehydrogenase activity, and thereby regulates metabolite flux through the tricarboxylic acid cycle, down-regulates aerobic respiration and inhibits the formation of acetyl-coenzyme A from pyruvate. Inhibition of pyruvate dehydrogenase decreases glucose utilization and increases fat metabolism. Mediates cellular responses to insulin. Plays an important role in maintaining normal blood glucose levels and in metabolic adaptation to nutrient availability. Via its regulation of pyruvate dehydrogenase activity, plays an important role in maintaining normal blood pH and in preventing the accumulation of ketone bodies under starvation. Plays a role in the regulation of cell proliferation and in resistance to apoptosis under oxidative stress. Plays a role in p53/TP53-mediated apoptosis. Ref.1 Ref.4 Ref.6 Ref.7 Ref.8

Catalytic activity

ATP + [pyruvate dehydrogenase (acetyl-transferring)] = ADP + [pyruvate dehydrogenase (acetyl-transferring)] phosphate. Ref.1 Ref.3 Ref.4 Ref.7 Ref.8 Ref.10

Enzyme regulation

Activity increases in response to increased acetyl-CoA and NADH levels and upon binding to the pyruvate dehydrogenase subunit DLAT. Inhibited by ADP and pyruvate; these compounds interfere with DLAT binding and thereby inhibit kinase activity. Inhibited by dichloroacetate. Inhibited by AZD7545; this compound interferes with DLAT binding and thereby inhibits kinase activity. Reactive oxygen species cause the formation of disulfide bonds, and thereby inhibit the enzyme. Ref.3 Ref.8

Subunit structure

Homodimer, and heterodimer with PDK1. Interacts with the pyruvate dehydrogenase complex subunit DLAT, and is part of the multimeric pyruvate dehydrogenase complex that contains multiple copies of pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (DLAT, E2) and lipoamide dehydrogenase (DLD, E3). Ref.5 Ref.7 Ref.10

Subcellular location

Mitochondrion matrix Ref.8.

Tissue specificity

Detected in heart (at protein level). Highest level of expression in heart and skeletal muscle and the lowest in spleen and lung. Liver, kidney, brain and testis levels are intermediate. Ref.1 Ref.3 Ref.8

Sequence similarities

Belongs to the PDK/BCKDK protein kinase family.

Contains 1 histidine kinase domain.

Ontologies

Keywords
   Biological processCarbohydrate metabolism
Glucose metabolism
   Cellular componentMitochondrion
   DomainTransit peptide
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processcellular response to nutrient

Inferred from sequence or structural similarity. Source: UniProtKB

glucose homeostasis

Inferred from sequence or structural similarity. Source: UniProtKB

glucose metabolic process

Inferred from electronic annotation. Source: UniProtKB-KW

insulin receptor signaling pathway

Inferred from sequence or structural similarity. Source: UniProtKB

peptidyl-serine phosphorylation

Inferred from direct assay Ref.4. Source: UniProtKB

regulation of acetyl-CoA biosynthetic process from pyruvate

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of gluconeogenesis

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of pH

Inferred from sequence or structural similarity. Source: UniProtKB

   Cellular_componentmitochondrial pyruvate dehydrogenase complex

Inferred from sequence or structural similarity. Source: UniProtKB

   Molecular_functionATP binding

Inferred from direct assay Ref.7PubMed 15312755Ref.3. Source: RGD

protein complex binding

Inferred from direct assay Ref.7. Source: RGD

protein heterodimerization activity

Inferred from direct assay Ref.7. Source: RGD

protein homodimerization activity

Inferred from direct assay Ref.7. Source: RGD

protein serine/threonine kinase activity

Inferred from direct assay Ref.4. Source: UniProtKB

pyruvate dehydrogenase (acetyl-transferring) kinase activity

Inferred from direct assay Ref.4. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Transit peptide1 – ?Mitochondrion Potential
Chain? – 407[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrialPRO_0000023442

Regions

Domain135 – 364230Histidine kinase
Nucleotide binding251 – 2588ATP
Nucleotide binding309 – 3102ATP
Nucleotide binding325 – 3306ATP

Sites

Binding site2901ATP

Secondary structure

.................................................... 407
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q64536 [UniParc].

Last modified November 1, 1996. Version 1.
Checksum: A01C377290A69EF4

FASTA40746,106
        10         20         30         40         50         60 
MRWFRALLKN ASLAGAPKYI EHFSKFSPSP LSMKQFLDFG SSNACEKTSF TFLRQELPVR 

        70         80         90        100        110        120 
LANIMKEINL LPDRVLSTPS VQLVQSWYVQ SLLDIMEFLD KDPEDHRTLS QFTDALVTIR 

       130        140        150        160        170        180 
NRHNDVVPTM AQGVLEYKDT YGDDPVSNQN IQYFLDRFYL SRISIRMLIN QHTLIFDGST 

       190        200        210        220        230        240 
NPAHPKHIGS IDPNCSVSDV VKDAYDMAKL LCDKYYMASP DLEIQEVNAT NATQPIHMVY 

       250        260        270        280        290        300 
VPSHLYHMLF ELFKNAMRAT VESHESSLTL PPIKIMVALG EEDLSIKMSD RGGGVPLRKI 

       310        320        330        340        350        360 
ERLFSYMYST APTPQPGTGG TPLAGFGYGL PISRLYAKYF QGDLQLFSME GFGTDAVIYL 

       370        380        390        400 
KALSTDSVER LPVYNKSAWR HYQTIQEAGD WCVPSTEPKN TSTYRVS 

« Hide

References

« Hide 'large scale' references
[1]"Molecular cloning of the p45 subunit of pyruvate dehydrogenase kinase."
Popov K.M., Kedishvili N.Y., Zhao Y., Gudi R., Harris R.A.
J. Biol. Chem. 269:29720-29724(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], CATALYTIC ACTIVITY, FUNCTION, TISSUE SPECIFICITY.
Tissue: Heart.
[2]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Prostate.
[3]"Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex."
Bowker-Kinley M.M., Davis W.I., Wu P., Harris R.A., Popov K.M.
Biochem. J. 329:191-196(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: CATALYTIC ACTIVITY, ENZYME REGULATION, TISSUE SPECIFICITY.
[4]"Site specificity of four pyruvate dehydrogenase kinase isoenzymes toward the three phosphorylation sites of human pyruvate dehydrogenase."
Korotchkina L.G., Patel M.S.
J. Biol. Chem. 276:37223-37229(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: CATALYTIC ACTIVITY, FUNCTION.
[5]"Interaction between the individual isoenzymes of pyruvate dehydrogenase kinase and the inner lipoyl-bearing domain of transacetylase component of pyruvate dehydrogenase complex."
Tuganova A., Boulatnikov I., Popov K.M.
Biochem. J. 366:129-136(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH DLAT.
[6]"AZD7545, a novel inhibitor of pyruvate dehydrogenase kinase 2 (PDHK2), activates pyruvate dehydrogenase in vivo and improves blood glucose control in obese (fa/fa) Zucker rats."
Mayers R.M., Butlin R.J., Kilgour E., Leighton B., Martin D., Myatt J., Orme J.P., Holloway B.R.
Biochem. Soc. Trans. 31:1165-1167(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[7]"Formation of functional heterodimers by isozymes 1 and 2 of pyruvate dehydrogenase kinase."
Boulatnikov I., Popov K.M.
Biochim. Biophys. Acta 1645:183-192(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: CATALYTIC ACTIVITY, FUNCTION, INTERACTION WITH PDK1, SUBUNIT.
[8]"Inactivation of pyruvate dehydrogenase kinase 2 by mitochondrial reactive oxygen species."
Hurd T.R., Collins Y., Abakumova I., Chouchani E.T., Baranowski B., Fearnley I.M., Prime T.A., Murphy M.P., James A.M.
J. Biol. Chem. 287:35153-35160(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, ENZYME REGULATION, TISSUE SPECIFICITY.
[9]"Structure of pyruvate dehydrogenase kinase. Novel folding pattern for a serine protein kinase."
Steussy C.N., Popov K.M., Bowker-Kinley M.M., Sloan R.B. Jr., Harris R.A., Hamilton J.A.
J. Biol. Chem. 276:37443-37450(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) IN COMPLEX WITH ADP.
[10]"Structural and functional insights into the molecular mechanisms responsible for the regulation of pyruvate dehydrogenase kinase 2."
Green T., Grigorian A., Klyuyeva A., Tuganova A., Luo M., Popov K.M.
J. Biol. Chem. 283:15789-15798(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) IN COMPLEX WITH ATP ANALOG AND DLAT, CATALYTIC ACTIVITY, SUBUNIT.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U10357 mRNA. Translation: AAB54084.1.
BC061823 mRNA. Translation: AAH61823.1.
PIRA55305.
RefSeqNP_110499.1. NM_030872.1.
UniGeneRn.88597.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1JM6X-ray2.50A/B1-407[»]
3CRKX-ray2.30A/B1-407[»]
3CRLX-ray2.61A/B1-407[»]
ProteinModelPortalQ64536.
SMRQ64536. Positions 12-404.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

IntActQ64536. 1 interaction.
STRING10116.ENSRNOP00000005641.

Chemistry

BindingDBQ64536.
ChEMBLCHEMBL2096663.

Proteomic databases

PaxDbQ64536.
PRIDEQ64536.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

GeneID81530.
KEGGrno:81530.
UCSCRGD:69428. rat.

Organism-specific databases

CTD5164.
RGD69428. Pdk2.

Phylogenomic databases

eggNOGCOG0642.
HOGENOMHOG000164315.
HOVERGENHBG000511.
InParanoidQ64536.
KOK00898.

Gene expression databases

GenevestigatorQ64536.

Family and domain databases

Gene3D1.20.140.20. 1 hit.
3.30.565.10. 1 hit.
InterProIPR018955. BCDHK/PDK_N.
IPR003594. HATPase_ATP-bd.
IPR005467. Sig_transdc_His_kinase_core.
[Graphical view]
PfamPF10436. BCDHK_Adom3. 1 hit.
PF02518. HATPase_c. 1 hit.
[Graphical view]
SMARTSM00387. HATPase_c. 1 hit.
[Graphical view]
SUPFAMSSF55874. SSF55874. 1 hit.
SSF69012. SSF69012. 1 hit.
PROSITEPS50109. HIS_KIN. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceQ64536.
NextBio615077.

Entry information

Entry namePDK2_RAT
AccessionPrimary (citable) accession number: Q64536
Entry history
Integrated into UniProtKB/Swiss-Prot: July 15, 1998
Last sequence update: November 1, 1996
Last modified: January 22, 2014
This is version 113 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references